Abstract

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the 'iCOGS' genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84-0.87; P=1.7 × 10(-43)) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

Authors	Ghoussaini, Maya; Edwards, Stacey L.; Michailidou, Kyriaki; Nord, Silje; Lari, Richard Cowper-Sal; Desai, Kinjal; Kar, Siddhartha; Hillman, Kristine M.; Kaufmann, Susanne; Glubb, Dylan M.; Beesley, Jonathan; Dennis, Joe; Bolla, Manjeet K.; Wang, Qin; Dicks, Ed; Guo, Qi; Schmidt, Marjanka K.; Shah, Mitul; Luben, Robert; Brown, Judith; Czene, Kamila; Darabi, Hatef; Eriksson, Mikael; Klevebring, Daniel; Bojesen, Stig E.; Nordestgaard, Borge G.; Nielsen, Sune F.; Flyger, Henrik; Lambrechts, Diether; Thienpont, Bernard; Neven, Patrick; Wildiers, Hans; Broeks, Annegien; Van't Veer, Laura J.; Rutgers, Emiel J.; Couch, Fergus J.; Olson, Janet E.; Hallberg, Emily; Vachon, Celine; Chang-Claude, Jenny; Rudolph, Anja; Seibold, Petra; Flesch-Janys, Dieter; Peto, Julian; dos-Santos-Silva, Isabel; Gibson, Lorna; Nevanlinna, Heli; Muranen, Taru A.; Aittomaki, Kristiina; Blomqvist, Carl; Hall, Per; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K.; Noh, D-Y; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Yatabe, Yasushi; Guenel, Pascal; Truong, Therese; Menegaux, Florence; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Schneeweiss, Andreas; Sohn, Christof; Wu, Anna H.; Tseng, Chiu-Chen; Van Den Berg, David J.; Stram, Douglas; Benitez, Javier; Pilar Zamora, M.; Arias Perez, Jose Ignacio; Menendez, Primitiva; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Qiuyin; Cox, Angela; Cross, Simon S.; Reed, Malcom W.; Andrulis, Irene L.; Knight, Julia A.; Glendon, Gord; Tchatchou, Sandrine; Sawyer, Elinor J.; Tomlinson, Ian; Kerin, Michael J.; Miller, Nicola; Haiman, Christopher A.; Henderson, Brian E.; Schumacher, Fredrick; Le Marchand, Loic; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Lee, Daphne S. C.; Wong, Tien Y.; Hooning, Maartje J.; Martens, John W. M.; Collee, J. Margriet; van Deurzen, Carolien H. M.; Hopper, John L.; Southey, Melissa; Tsimiklis, Helen; Kapuscinski, Miroslav K.; Shen, Chen-Yang; Wu, Pei-Ei; Yu, Jyh-Cherng; Chen, Shou-Tung; Alnaes, Grethe Grenaker; Borresen-Dale, Anne-Lise; Giles, Graham G.; Milne, Roger L.; McLean, Catriona A.; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Buhari, Shaik A.; Fasching, Peter A.; Haeberle, Lothar; Ekici, Arif B.; Beckmann, Matthias W.; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Swerdlow, Anthony J.; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk; Garcia-Closas, Montserrat; Figueroa, Jonine; Chanock, Stephen; Lissowska, Jolanta; Simard, Jacques; Goldberg, Mark S.; Labreche, France; Dumont, Martine; Winqvist, Robert; Pylkas, Katri; Jukkola-Vuorinen, Arja; Brauch, Hiltrud; Bruning, Thomas; Koto, Yon-Dschun; Radice, Paolo; Peterlongo, Paolo; Bonanni, Bernardo; Volorio, Sara; Doerk, Thilo; Bogdanova, Natalia; Helbig, Sonja; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana; Devilee, Peter; Tollenaar, Rob A. E. M.; Seynaeve, Caroline; van Asperen, Christi J.; Jakubowska, Anna; Lubinski, Jan; Jaworska-Bieniek, Katarzyna; Durda, Katarzyna; Slager, Susan; Toland, Amanda Ewart; Ambrosone, Christine B.; Yannoukakos, Drakoulis; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; Mckay, James; Hamann, Ute; Torres, Diana; Zheng, W.; Long, Jirong; Anton-Culver, Hoda; Neuhausen, Susan L.; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Maranian, Mel J.; Healey, Catherine S.; Gonzalez-Neira, Anna; Pita, Guillermo; Alonso, M. Rosario; Alvarez, Nuria; Herrero, Daniel; Tessier, Daniel C.; Vincent, Daniel; Bacot, Francois; de Santiago, Ines; Carroll, Jason; Caldas, Carlos; Brown, M; Lupien, Mathieu; Kristensen, Vessela N.; Pharoah, Paul D. P.; Chenevix-Trench, G; French, Juliet D.; Easton, Douglas F.; Dunning, Alison M.
Journal	Nature Communications
Pages	4999
Volume	23
Date	1/09/2014
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/ncomms5999